DNA Replication Linked to Chemotherapy Resistance in Breast Cancer

An unexpected process for developing chemotherapy resistance in breast cancer was found in a recent study.

Normally, BRCA1 and BRCA2 proteins act as DNA damage sensors, surveyors, and responders. The role of these proteins is to help perform complex functions that facilitate the repair of damaged DNA, according to a study published in Nature.

However, individuals who inherit certain mutations in either of the genes have an increased risk of breast, ovarian, and other cancers.

BRCA1 and BRCA2 mutations account for 20% to 25% of hereditary breast cancers, and 5% to 10% of all breast cancers. Since these mutations show a reduced ability to repair damaged DNA, it causes the cells to become sensitive to DNA damaging drugs; however, breast cancer cells eventually build up resistance to these chemotherapy drugs.

There is one documented mechanism for drug resistance in tumors, through the restoration of accurate DNA repair pathways that mend DNA breaks caused by chemotherapy.

“It is the intricate mechanisms that tumor cells evolve to bypass the need for accurate DNA repair that form the foundation of our study,” said researcher Andre Nussenzweig, PhD. “A deeper knowledge of the processes that drive drug resistance in -mutant tumors will lead to novel therapeutic approaches that target tumor-specific vulnerabilities.”

The researchers linked the protection and stabilization of DNA replication forks as a major contributing mechanism to chemotherapy resistance in BRCA1/2 mutant breast and ovarian cancers. When the replication fork migration is interrupted, it is referred to as a stalled fork.

During replication fork stalling, the BRCA1/2 proteins are called on to protect the newly synthesized DNA strands. However, when the proteins are missing, the replication fork is destabilized and the newly synthesized DNA becomes degraded.

This causes an increase in genomic instability, and increases the sensitivity to DNA damaging drugs. Further findings allowed researchers to identify additional proteins, such as PTIP, CHD4, and PARP1, which actively promote replication fork destabilization by recruiting enzymes that degrade newly synthesized DNA.

When these proteins were absent, it protected the DNA at replication forks, and reversed the drug sensitivity of BRCA1 and BRCA2 mutant cells, causing them to become chemoresistant. The findings also highlighted the complexity of tumor cells that are able to evade chemotherapy and develop drug resistance, since disrupting the activity of several proteins caused the same end point of replication fork protection.

Authors noted that the results are especially relevant in the clinical setting, because the expression of the proteins seem to be an indicator of how patients with the BRCA1/2 mutations will respond to chemotherapy.

“Our work is starting to not only refine, but also redefine, the current dogma in the field, which states that restoring DNA repair pathways are the only means by which BRCA1/2-mutant cells can become chemoresistant,” Nussenzweig said.